Transcriptional control of adipogenesis in vivo is a complex process involving a large number of genes and phenotype specific as well as general regulatory proteins. Many of these factors, their cognate elements and their functional co-factors are all present in a rate limiting concentration, and must assemble into distinct multi-component regulatory complexes to selectively activate or suppress target genes in response to physiological and developmental cues. Age related changes result in increased adiposity in the musculoskeletal system and concomitant decreased activity of bone-forming osteoblast and thus represent a potentially serious health risk. Key regulators of adipogenesis, lipid and glucose homeostasis have been identified and include members of the CAATT enhancer binding protein (C/EBP) family and peroxisome proliferator-activated receptor (PPAR). Null mutation of these factors results in lethality and loss of adipogenesis. Similarly, Runx2/Cbfa1 is an obligatory factor for osteoblast differentiation and bone formation during embryonic development. Runx2 gene ablation cause complete failure of skeleton formation and results in embryonic lethality. Recent finding indicates an inverse relationship between the numbers of adipocytes and osteoblasts in bone during aging and in pathological conditions. However it is unclear why aging leads to adipogenesis. Osteoblasts and adipocytes originate from a common progenitor which arises from mesenchymal stroma/stem cells in marrow. Thus, Runx2 represent a paradigm to functionally address the enhanced adipogenesis at the expense of osteogenesis in aging subjects. Our proposed studies will address molecular mechanisms involved in this switch by a regulated ablation of the Runx2 protein, or expression of a mutant Runx2 protein that is compromise in its ability to negatively regulate adipocytic differentiation using both ex-vivo and in vivo mouse models. We hypothesized that Runx2 functional activity to "prime" progenitor cells to osteoblasts is altered in aging skeleton thus favoring differentiation towards adipocytes. Our long term objectives are to identify molecular mechanisms regulating the differential/bi-polar activities of Runx2 during adipocytic and osteogenic differentiation. These studies may be translated to novel therapies for congenital and degenerative skeletal diseases, metabolic bone disorders and aging. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]